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Cancer therapy targets secretory pathways

Secretion is a fundamental cellular process. Defects in the secretory pathway have been associated with certain genetic diseases in which the maturation of proteins is disturbed. Non-genetic diseases such as metabolic disorders and cancer have also been linked to a defective secretory pathway. Dr. Hesso Farhan from the University of Konstanz and the Biotechnology Institute Thurgau (BITg) is investigating possible ways to counteract the development and spread of tumours by interfering with the secretory pathway. Using an innovative method, Farhan’s team of researchers has discovered migration inhibitors, which would otherwise have gone undetected.

The Golgi apparatus is involved in the secretory pathway and is a key component of eukaryotic cells that is important in the processing of proteins for secretion as well as in other metabolic processes. It is composed of stacks of cisternae. “The membranes of the cisternae contain enzymes involved in the post-translational modification of proteins, for example the attachment of carbohydrates, which are extremely important for the maturation of proteins,” explains Dr. Hesso Farhan.

In addition to focusing on the classical role of the Golgi apparatus in the maturation of proteins, Dr. Farhan’s research also takes into account more recent findings about other cellular functions of the Golgi apparatus, for example the role it plays in the transmission of signals and in cell migration, a process that enables metastases to move away from the primary site of the tumour and spread around the body. 

 “If we can find out how to prevent tumour cells from moving away from the original site of tumour, we will also be able to develop drugs that specifically target metastases. Given in combination with chemotherapy, we believe that such drugs will contribute to increasing the survival rate of cancer patients,” said the biologist from the University of Konstanz highlighting that up to 90 per cent of cancer-related deaths are caused by metastases.

Dr. Hesso Farhan with his group of researchers
Dr. Hesso Farhan with his group of researchers. © Hesso Farhan

Golgi apparatus controls cell migration

Farhan’s team has shown that the connections between signal transduction, Golgi apparatus and cell migration are more complex than assumed previously. The Golgi apparatus is controlled by cellular signals at the same time as it affects them. The Golgi apparatus is not just a passive recipient, but also actively controls cellular signalling. It can therefore be assumed that it plays a primary role in the migration of cells. By concentrating on research into the secretory pathway, Dr. Hesso Farhan hopes to clarify whether directional cell migration can be inhibited. At present, investigations are in full flow. “We believe that research into the secretory pathway is a promising approach for combating cancer,” said the biologist.

A new approach for identifying migration inhibitors

In his effort to identify targets that enable the inhibition of directional cell migration, Dr. Farhan is pursuing a different path to that taken by traditional research. “We are using a strategy that is focused on the Golgi apparatus. We initially tested the effect of the inhibitors on the structure of the Golgi apparatus and then went on to focus on cell migration.” This strategy enabled Farhan and his team to identify regulators that would have gone undetected using traditional approaches. Farhan and his team use small interfering RNAs (siRNA) for investigating the role of a particular protein. siRNAs are synthetic RNA molecules designed to suppress the production of proteins through the mechanism of RNA interference. “The classical approach is to investigate the function of proteins by overexpressing the proteins under investigation. This means that a cell is made to produce between 10 and 20 times the normal quantity of a particular protein,” said Dr. Farhan going on to explain that this approach leads to inaccuracies and has often led to wrong conclusions.

Left: Control cell (left) with a compact Golgi apparatus. The Golgi apparatus has been visualized using the immunofluorescent staining of giantin, which is the largest Golgi membrane protein. The photo on the right shows a cell in which a particular protein was silenced (using siRNA); this strongly interferes with the structural integrity of the Golgi apparatus. Dr. Farhan’s research group calls proteins that regulate the structural integrity of the Golgi apparatus “Golgi-class hits”. The Golgi apparatus of this cell has also been visualized using immunofluorescent staining of giantin. The photos were taken using a confocal laser scanning microscope.
Left: Control cell (left) with a compact Golgi apparatus. The Golgi apparatus has been visualized using the immunofluorescent staining of giantin, which is the largest Golgi membrane protein. The photo on the right shows a cell in which a particular protein was silenced (using siRNA); this strongly interferes with the structural integrity of the Golgi apparatus. Dr. Farhan’s research group calls proteins that regulate the structural integrity of the Golgi apparatus “Golgi-class hits”. The Golgi apparatus of this cell has also been visualized using immunofluorescent staining of giantin. The photos were taken using a confocal laser scanning microscope. © Hesso Farhan

Dr. Farhan and his group of researchers are investigating the effect the combination of the overexpression of specific proteins and the knock-down of Golgi-class hits using siRNA have on the structural integrity of the Golgi apparatus. The researchers use confocal laser scanning microscopes for their investigations and have found that in the majority of cases, interfering with the morphology of the Golgi apparatus results in an inhibition of directional cell migration. They also identified a protein that, when silenced, leads to the inhibition of cell migration. This protein would therefore seem to be a promising target for the treatment of metastasing tumours. Farhan and his researchers have analysed more than 100 proteins and tested their interactions with the Golgi apparatus and signalling transduction.

It is still too early to be able to tell when the group’s findings will be integrated into existing anti-cancer treatment concepts or when they will open up new therapeutic strategies for the treatment of tumours. “I would be satisfied with our work if at some stage in the future I could say that our findings have helped to cure a cancer patient because they contributed to the development of a new therapeutic strategy,” concluded Dr. Farhan.

Further information:
Biotechnology Institute Thurgau
Faculty of Biology
University of Konstanz
Unterseestrasse 47
CH-8280 Kreuzlingen
Switzerland
Tel.: +41 (0)71 678 5027
Fax: +41 (0)71 678 5021
E-mail: hesso.farhan(at)uni-konstanz.de
Web: www.bitg.ch/DWresearch_Farhan.html

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/cancer-therapy-targets-secretory-pathways